Early high-dose Rosuvastatin for Contrast-Induced Nephropathy Prevention in Acute Coronary Syndrome The PRATO-ACS (Protective effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome) Study Anna Toso, MD on behalf of the PRATO-ACS investigators PRATO-ACS study

Principal investigator: Co-Investigators: Anna Toso Mario Leoncini Mauro Maioli Francesco Tropeano Francesco Bellandi Cardiology Division of Misericordia e Dolce Hospital, Prato, Italy Site management & monitoring: Hospital Ethics Committee Data management: Biostatistics: Centro Cardiopatici Toscani (non-profit organization) Simona Villani Section of Biostatistics and Clinical Epidemiology, Pavia University, Italy Financial support: no external financial support Trial Registration clinicaltrial.gov Identifier: NCT01185938 PRATO-ACS study

Contrast Nephropathy Role of Statins Uncertainties include: Anti-lipidemic and pleiotropic properties (anti-oxidant, anti-inflammatory, anti-thrombotic) may have a nephro-protective effect improving endothelial function and reducing oxidative stress. Uncertainties include: -type and dose -timing -target population PRATO-ACS study

for CI-AKI prevention in ACS patients Study Hypothesis On-admission high-dose statins for CI-AKI prevention in ACS patients Does early high-dose hydrophilic statin rosuvastatin -in addition to standard preventive measures (hydration and N-acetylcystein)- exert beneficial effects against CI-AKI in statin-naïve patients with NSTE-ACS scheduled for early invasive strategy? PRATO-ACS study

All consecutive statin-naïve NSTE-ACS patients Methods Inclusion criteria All consecutive statin-naïve NSTE-ACS patients admitted to CCU and scheduled for early invasive strategy Study period: July 2010-August 2012 PRATO-ACS study

Emergency (within 2 hrs) angiography Methods Exclusion criteria Emergency (within 2 hrs) angiography Acute renal failure or ESRD requiring dialysis Baseline serum creatinine ≥ 3 mg/dl Contraindications to statin treatment Contrast administration within the last 10 days Refusal to consent • PRATO-ACS study

Methods Study Design Statin-naive & Early Invasive Strategy NSTE-ACS patients R CCU-Admission Rosuvastatin 40 mg (LD) then 20 mg/day Hydration, N-Acetylcystein Controls ~ 24 H Coronary Angiography ± PCI Primary Endpoint: ↑ Cr ≥ 0.5 mg/dl or ≥ 25 % within 72 hrs of contrast exposure Contrast CI-AKI 72 H Sample size: assumed 18% CI-AKI in control and 50% reduction in treatment. With a 80% statistical power and 2-sided type 1 error of 5%; 15% drop out  ~ 540 pts

Additional End-points Methods Additional End-points 1. CI-AKI defined by other criteria: ↑ Cr ≥ 25 % or ≥ 0.5 mg/dl within 48 hrs ↑ Cr ≥ 0.3 mg/dl within 48 hrs ↑ Cr ≥ 0.5 mg/dl within 72 hrs ↑ Cr ≥ 0.3 mg/dl within 72 hrs ↓ eGFR ≥ 25% within 72 hrs PRATO-ACS study

Methods Additional End-points 2. CI-AKI in pre-specified subgroups Age < or  70 yrs Gender Diabetes mellitus Creatinine Clearance < / ≥ 60 ml/min LV-EF ≤ / > 45% CI-AKI Mehran risk score ≤ / > 5 Contrast volume administered ≤ / > 140 ml PCI procedure Clinical Risk Level (at least one of the following): Age ≥ 70 Diabetes mellitus Creatinine Clearance < 60 ml/min LV-EF ≤ 45%

Additional End-points Methods Additional End-points 3. Adverse Clinical Events (30 days): Acute renal failure requiring dialysis Persistent renal damage* All-causes mortality Myocardial infarction Stroke *↓ eGFR ≥ 25% within 1 month in CI-AKI pts PRATO-ACS study

Antiplatelet treatment: Methods Additional Protocol Details Antiplatelet treatment: ASA (300 mg LD, 100 mg/day MD) Clopidogrel (600 mg LD, 150 mg/day→ discharge) • Hydration i.v.12 hrs pre and post contrast medium (isotonic saline 1 ml/kg/h or 0.5 ml/kg/h if LV-EF < 40% ) Oral N-Acetylcystein 24 hrs pre and post contrast medium (2400 mg/day) Nonionic, dimeric iso-osmolar contrast medium (Iodixanol) & Power injector (ACIST) At discharge: Clopidogrel 75 mg/day, ASA 100 mg/day & Rosuvastatin group Rosuvastatin 20 mg/day (10 mg/day if CrCL< 30 ml/min) Controls Atorvastatin 40 mg/day Discharge

Statin-naive & Early Invasive Strategy NSTE-ACS patients Study Flow Statin-naive & Early Invasive Strategy NSTE-ACS patients Randomized n = 543 Rosuvastatin n = 271 Excluded = 19 no angiography = 9 no 72 hrs creatinine = 10 CI-AKI analysis n = 252 Controls n = 272 Excluded = 20 no angiography = 8 no 72 hrs creatinine = 12 CI-AKI analysis n = 252

Baseline Characteristics Clinical and Demographic Rosuvastatin 66.2 ± 12.4 46.4 34 26.2 ± 3.7 Control 66.1 ± 13.5 44.8 34 26.6 ± 4.4 p value 0.91 0.72 0.93 0.35 Age Age ≥ 70 years.% Female, % Body Mass Index Clinical presentation, % NSTE-MI Unstable angina 92.4 7.5 92.1 7.9 >0.90 Risk factors, % Hypertension Diabetes mellitus Creatinine clearance < 60ml/min Previous MI Previous PCI or CABG Baseline LV EF (%) EF < 45% High Clinical Risk Level, % 56.7 19.8 41.7 9.5 11.9 50 ± 9 33.3 71.4 54.8 22.6 41.7 5.9 7.1 50 ± 9 33.7 67.1 0.65 0.45 >0.90 0.13 0.07 0.93 0.29

Baseline Characteristics Biochemical Rosuvastatin 0.95 ± 0.27 69.9 ± 24.4 14.1 ± 1.6 0.43 (0.21-1.18) 2.3 ± 5.1 19.2 ± 3 5.2 135.2 ± 38.6 40.2 ±13.7 119.7 ± 62.8 131.7 ± 50.1 Control 0.96 ± 0.28 69.3 ± 24.9 14.1 ± 1.6 0.52 (0.20-1.28) 2.5 ± 7.0 23.1 ± 48.8 135.8 ± 42.7 42.3 ± 13.3 118 ± 73 137.3 ± 53.4 p value 0.89 0.81 0.77 0.57 0.41 0.34 0.85 0.08 0.78 0.23 Serum creatinine (mg/dl) Creatinine Clearance (ml/min) Haemoglobin (mg/dl) hs-CRP (mg/dl) cTn-I (ng/ml) CK-MB (ng/ml) LDL - Cholesterol (mg/dl) HDL - Cholesterol (mg/dl) Triglycerides (mg/dl) Glycaemia (mg/dl)

Procedural data Rosuvastatin 22.5 (14 – 43) 48.8 149.7 ± 86.8 46.4 21.4 10.7 67.9 Control 23 (15 – 45.5) 47.6 138.2 ± 77.8 40.1 23.8 11.9 64.3 p value 0.79 0.78 0.14 0.15 0.70 Randomization-to-Contrast time (hrs) Multivessel disease, % Contrast volume (ml) Contrast volume >140 ml Therapeutic strategy, % Medical treatment CABG PCI PCI data Multivessel PCI Contrast volume (ml) Contrast volume >140 ml, % CI-AKI Mehran risk score, median (IQR) ≤ 5, % >5, % 33.9 183 ± 80 64.9 3 (1 – 6) 74.2 25.8 28.3 172 ± 72 59.8 2 (1 – 5) 76.6 23.4 0.21 0.18 0.20 0.36

CI-AKI Primary Endpoint ( 0.5 or  25% within 72 hrs) ORcrude (95% CI): 0.41 (0.22 - 0.74) ORadjusted (95% CI): 0.38 (0.20 – 0.71) NNT = 12 *Adjusted for: Sex, Age, Diabetes, Hypertension, LDL-cholesterol, Creatinine Clearance, LV-EF, Contrast Volume, CI-AKI Risk Score PRATO-ACS study

Additional Endpoints: 1.Different CI-AKI criteria PRATO-ACS study

Additional Endpoints: 2.Pre-specified Subgroups

3. Adverse Clinical Events (30 days) Additional Endpoints: 3. Adverse Clinical Events (30 days) PRATO-ACS study

Conclusions-1 In statin-naïve patients with NSTE-ACS scheduled for early invasive strategy on-admission high-dose rosuvastatin: •exerts additional preventive effects against CI-AKI (w/ hydration & N-Acetylcystein); •is associated to better short-term clinical outcome. PRATO-ACS study

This study suggests that in NSTE-ACS Conclusions-2 This study suggests that in NSTE-ACS patients scheduled for early invasive strategy high-dose statins should be given on admission and in any case must precede the angiographic procedure in order to reduce renal complications after contrast medium administration. PRATO-ACS study

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